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Pyrrolotriazinone Derivatives As PI3K Inhibitors

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Pyrrolotriazinone Derivatives As PI3K Inhibitors (19) & (11) EP 2 518 070 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 31.10.2012 Bulletin 2012/44 C07D 473/34 (2006.01) C07D 487/04 (2006.01) A61K 31/4985 (2006.01) A61K 31/437 (2006.01) (2006.01) (21) Application number: 11382124.3 A61P 35/00 (22) Date of filing: 29.04.2011 (84) Designated Contracting States: • Caturla Javaloyes, Juan Francisco AL AT BE BG CH CY CZ DE DK EE ES FI FR GB 08980, Sant Feliu de Llobregat (ES) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • Gracia Ferrer, Jordi PL PT RO RS SE SI SK SM TR 08980, Sant Feliu de Llobregat (ES) Designated Extension States: • Matassa, Victor Giulio BA ME 08980, Sant Feliu de Llobregat (ES) • Terricabras Belart, Emma (71) Applicant: Almirall, S.A. 08980, Sant Feliu de Llobregat (ES) 08022 Barcelona (ES) (74) Representative: Elzaburu Marquez, Alberto (72) Inventors: Elzaburu S.L.P. • Bernal Anchuela, Francisco Javier Miguel Angel 21 08980, Sant Feliu de Llobregat (ES) 28010 Madrid (ES) • Carrascal Riera, Marta 08980, Sant Feliu de Llobregat (ES) (54) Pyrrolotriazinone derivatives as PI3K inhibitors (57) New pyrrolotriazinone derivatives having the chem- ical structure of formula (I) are disclosed; as well as proc- ess for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Phosphoinositide 3-Kinases (PI3Ks) EP 2 518 070 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 518 070 A1 Description [0001] When cells are activated by extracellular stimuli, intracellular signalling cascades involving the regulation of second messengers are initiated that eventually produce a response of the cell to the stimuli. Phosphoinositide 3- Kinases 5 (PI3Ks) are among the enzymes involved in early signalling events to a plethora of different types of stimuli. PI3Ks phosphorylate the 3-hydroxyl group of the inositol ring of phosphatidylinositol (PtdIns), Ptdlns-4- phosphate (PtdIns4P), and Ptdlns-4,5-bisphosphate (PtdIns(4,5)P2). The resulting 3-phosphoinositides mediate correct localization and sub- sequent activation of a number of downstream effector proteins that bind to the lipids via specific lipid binding sequences such as the pleckstrin homology (PH) domain (Vanhaesebroeck B, 2010, Nat Rev Mol Cell Biol 5:11381-6). 10 [0002] The PI3K family is divided into 3 different classes (PI3K class I, class II, and class III), depending on substrate preference and structural features. [0003] The best characterized is the PI3K class I with the preferential substrate Ptdlns-(4,5) P2. It englobes 4 different isoforms which originally were further subdivided into class IA (p110a, p110b, p110d), binding to a p85 type of regulatory subunit, and class IB (p110g) which is regulated by p101 and p87 subunits. Whereas p110a (PI3Ka or PI3K α) and p110b 15 (Pl3Kb or PI3Kβ) isoforms are expressed ubiquitously, p110g (PI3Kg or PI3Kγ) and especially p110d (PI3Kd or PI3Kδ) have a more restricted expression pattern and seem to play a major role in leukocytes (Kok K, Trends Biochem Science 34:115-127, 2009). [0004] Both, PI3Kd and PI3Kg are involved in activation of immune cells by a large variety of different stimuli. Phar- macological inhibition or genetic deficiency in active p110d has been shown to inhibit T cell proliferation and cytokine 20 production in response to different stimuli such as anti- CD3, anti-CD3/CD28, superantigen or antigen in vitro (Ji H, Blood 2007; Okkenhaug K, Science 2002; Garcon F, 2009; Soond DR, Blood 2010; Herman SEM, Blood June 3, 2010; William O, Chemistry & Biology 17, 2010) and to suppress concanavalin A and anti-CD3 induced cytokine production as well as antigen-dependent tissue retention in vivo (Soond DR, Blood 2010; Jarmin SJ, JCI 2008). In addition, B cell function is critically dependent on functional PI3Kd activity as demonstrated by suppressed B cell proliferation and cytokine 25 release in vitro in response to anti-IgM (Bilancio A, Blood 107, 2006), toll like receptor agonists such as LPS and oligodeoxynucleotides (Dil N, Mol Immunol 46, 2009) or impaired ability to stimulate antigen-specific T cells (Al-Alwan M, JI 2007) in the absence of functional p110d or pharmacological inhibition. In vivo, PI3Kg deficient mice display partially suppressed antibody production upon immunization (Garcon F, 2009; Durand CA, JI 2009). Further studies have dem- onstrated an important role of PI3Kd in inhibition of T cell apoptosis and in TH17 differentiation (Haylock-Jacobs S, J. 30 Autoimmun 2010). [0005] In addition, mast cell degranulation was reduced in cells from mice with inactivated PI3Kd or by pharmacological inhibition of PI3Kd (Ali K, Nature 431: 1007-1011, 2004; Ali K, Journal of Immunology 180: 2538-2544, 2008) and basophil activation via the FcE receptor is suppressed by pharmacological inhibition of PI3Kd (Lannutti BJ, Blood Oct. 2010). [0006] In terms of neutrophil function, PI3Kd inhibition inhibits migration of mouse neutrophils to fMLP in an under- 35 agarose migration assay by inhibiting cell polarization and directional movement (Sadhu C, JI 170, 2003) and mouse PI3Kd deficient or inhibitor treated neutrophils show slightly (25%) reduced in vitro chemotaxis to LTB4, whereas in vivo accumulation in the lung in response to LPS was reduced by more than 80%, indicating an important role of PI3Kd in endothelial cells for mediating PMN transendothelial migration (Puri KD, Blood 103, 2004). Furthermore, TNF induced neutrophil infiltration to an air pouch in mice and elastase release is partially inhibited by a PI3Kd selective inhibitor 40 (Sadhu C, Biochem Biophys Res Comm 308, 2003). In addition, TNF mediated priming of oxidative burst by human neutrophils depends on PI3Kd activity (Condliffe AM, Blood 106, 2005). [0007] In contrast to the dominant role of PI3Kd in lymphocyte activation, PI3Kg seems to affect primarily chemotaxis of different immune cells induced by various mediators and chemokines (Martin AL, JI 180, 2008; Thomas MS, J Leukoc Biol 84, 2008; Jarmin SJ, JCI 2008; Matthew T, Immunology 126, 2008), as well as degranulation and oxidative burst 45 of innate immuce cells induced by GPCR mediated stimuli such as fMLP, IL-8 or C5a (Condliffe AM, Blood 106, 2005; Yum HK, JI 167, 2001; Pinho V, JI 179, 2007 [0008] The above mentioned findings suggest that selective PI3Kd or dual PI3Kd/PI3Kg pharmacological inhibition represents a promising approach for treating a variety of diseases such as respiratory diseases (asthma, chronic ob- structive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis), allergic diseases (allergic 50 rhinitis), inflammatory or autoimmune diseases (rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, myastenia gravias, acute disseminated encephalo- myelitis, idiopathic thromocytopenic purpura, Sjoegren’s syndrome, autoimmune hemolytic anemia, type I diabetes, psoriasis, acrodermatitis, angiodermatitis, atopic dermatitis, contact dermatitis, eczema, acne, chronic urticaria, blistering diseases including but not limited to bullous pemphigoid, scleroderma, dermatomyositis, etc.), cardiovascular diseases; 55 viral infection; metabolism/endocrine function disorders; neurological disorders and pain (such as pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain, inflammatory neuropathic pain, trigeminal neuralgia or central pain) as well as in bone marrow and organ transplant rejection; myelo-dysplastic syndrome; mye- loproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors (such 2 EP 2 518 070 A1 as pancreatic cancer; bladder cancer; colorectal cancer; breast cancer; prostate cancer; renal cancer; hepatocellular cancer; lung cancer; ovarian cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer; non- small cell lung cancer and small- cell lung cancer; melanoma; neuroendocrine cancers; central nervious system cancers; brain tumors; bone cancer; soft tissue sarcoma; chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia, T- 5 cell acute lymphoblastic leukaemia, non-hodgkins lymphoma, B-cell lymphoma, acute myeloid leukaemia; cutaneous T cell lymphoma, premalignant and malignant skin conditions including but not limited to basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or actinic keratosis (AK)). [0009] There is substantial experimental evidence supporting this view. In rodent models of allergic lung inflammation, genetic or pharmacolocical inactivation of PI3Kd or dual PI3Kd/g dual inhibition reduces cell influx, mucus production, 10 cytokine production and airway hyperreactivity (Nashed et a. 2007, Eur J Immunol 37:416; Lee et al. 2006, FASEB J 20:455 & Lee KS et al. 2006, J Allergy Clin Immunol 118:403; Doukas J, JPET 2009;328:758; Par SJ, ERJ 2010). Moreover, LPS induced lung neutrophil infiltration is blocked by PI3Kd inhibition (Puri KD, Blood 2004;103:3448) and inflammation in response to LPS or tobacco smoke exposure is suppressed by a dual PI3Kd/g inhibitor (Doukas J, JPET 2009;328:758). Moreover, PI3Kd seems to be involved in the reduction of responsiveness to corticosteroid treatment 15 associated with oxidative stress and chronic obstructive pulmonary disease (COPD). This notion is based on the findings that tobacco smoke induced inflammation remains responsive to treatment with budesonide, whereas wild type or PI3Kg deficient mice develop resistance to corticosteroid treatment (Marwick JA,
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